Ester intermediates for producing polyene compounds

ABSTRACT

A PROCESS FOR PRODUCING 3-METHYL-5-(1-HYDROXY-2,6,6TRIMETHYL - 4 - OXO-CYCLOHEX-2-EN-L-YL)-PENTA-2,4-DIEN-1OIC ACID, DERIVATIVES THEREOF AND RELATED COMPOUNDS WHICH ARE USEFUL AS PLANT GROWTH REGULATOR., FROM 4-(1,2-EPOXY2,6,6-TRIMETHYL-CYCLOHEX-3-EN-L-YL)-BUT-3-EN-2-ONE OR 3METHYL - 5 - (1,2-EPOXY-2,6,6-TRIMETHYL-CYCLOHEX-3-EN-1YL)-PENTA-2,4-DIENYL DERIVATIVES INCLUDING INTERMEDIATES IN THIS PROCESS.

United States Patent O 3,803,217 ESTER INTERMEDIATES FOR PRODUCINGPOLYENE COMPOUNDS Ulrich Schwieter, 8 Im Pfeifiengarten, Reinach, Basel-Land, Switzerland, and Norbert Rigassi, 3 Gehrenmattstrasse, Arlesheim,Switzerland No Drawing. Original application June 18, 1970, Ser. No.47,572. Divided and this application Mar. 19, 1973, Ser. No. 342,576Claims priority, application Switzerland, July 4, 1969, 10,221/ 69 Int.Cl. C07c 69/14, 69/62, 69/78, 70/46 US. Cl. 260-488 R 2 Claims ABSTRACTOF THE DISCLOSURE A process for producing 3-methyl-5-(lhydroxy-2,6,6-trimethyl 4 oxo-cyclohex-Z-en-l-yl)-penta-2,4-dien-loic acid,derivatives thereof and related compounds which are useful as plantgrowth regulators, from 4-(1,2-ep0xy-2,6,6-trimethyl-cyclohex-3-en-l-yl)-but-3-en-2-one or 3- methyl 5(l,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1- yl)-penta-2,4-dienylderivatives including intermediates in this process.

This is a division, of application Ser. No. 47,572 filed June 18, 1970.

BACKGROUND OF THE INVENTION In the past1-hydroxy-2,6,-6-trimethyl-4-oxocyclohexene compounds have beenmanufactured with difi'iculty and in poor yields. For example,4-(1-hydroxy-2,6,6-tri methyl 4 oxo-cyclohex-Z-en-l-yl) but-3-en-2-one[6 hydroxy-3-keto-a-ionone] has been prepared by oxidizing 4(2,6,6-trimethyl-cyclohex-Z-en-l-yl)but-3-en-2-one [aionone] witht-butyl chromate or chromic acid. This oxidation has only produced thedesired 6-hydroxy-3-keto-uionone in poor yields. Furthermore, the6-hydroxy-3-ketoa-ionone obtained by this process has been difiicult toisolate in pure form.

Additionally, the known plant growth regulator, abscisic acid,[3-methyl-5-(l-hydroxy-2,6,6-trimethyl-4-ox0-cyclohex-2-en-1-yl)-penta-2-cis,4-trans-dien 1 oic acid] has in the pastbeen prepared by first converting 3- methyl-S-(2,6,6-trimethyl-cyclohexa1,3 dien l y1)- penta-2,4-dien-l-oic acid into 3methyl5(1,4-epidioxy-2,6,6-trimethylcyclohex-2-en-l-yl)penta-2,4-dienoic acid by photochemicaloxidation, thenopening the endoperoxide with a base and thereafterseparating the desired Z-cis isomer from the 2-cis/trans isomericmixture. This process suffers from the disadvantage that it producesabscisic acid in poor yields and that extensive purification of theabscisic acid produced by this process is necessary.

SUMMARY OF THE INVENTION In accordance with this invention it has beenfound that compounds of the formula (I) wherein R is CH; CH=CHC-CH: orCH=CHC=CHX X is hydroxymethylene, formyl, cyano, carboxy, loweralkoxycarbonyl, lower alkanoyl, phenoxycarbonyl,

phenoxycarbonyl substituted with at least one member selected from thegroup consisting of nitro, lower alkyl, halo lower alkyl, or loweralkylsulfonyl, benzoyl, ben- 3,803,217 Patented Apr. 9, 1974 zoylsubstituted with at least one member selected from the group consistingof lower alkyl, nitro, halo lower alkyl or lower alkylsulfonyl, or

and R and R are individually hydrogen, lower alkyl or phenyl or takentogether with their attached nitrogen atom form an imidazole ring can beobtained in high yields and with a high degree of purity in a simplemanner by first reacting a compound of the formula (1 wherein R is and Rand R are individually hydrogen, lower alkyl or phenyl or taken togetherwith their attached nitrogen form an imidazole ring with seleniumdioxide and then oxidizing the resulting 1,4-diol. If the compound ofFormula I is formed where X is an etherified or esterifiedhydroxymethylene group; this group can be hydrolized to form thecorresponding alcohol. If the compound of Formula I above is formedwhere X is an esterified acid group, these esters can, if desired, besaponified and, if desired, the resulting acid converted into an amideor an ester.

In accordance with this invention, the above process provides a simpleand economic means for producing the known plant hormones such asabscisic acid, abscisic acid derivatives and related compounds asillustrated by Formula I above.

The compounds of Formula I are useful as plant growth regulatory agents.

Among the preferred compounds of Formula I produced by this inventionare the following:

4-( 1-hydroxy-2,6,G-trimethyl-4-oxo-cyclohex-2-en-1-y1) but-3-en-2-one[6-hydroxy-3-keto-a-ionone];

3-methyl-5- 1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-1-yl)-penta-2-cis,4-trans-dien-l-oic acid [abscisin];

3-methyl-5- 1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex--2-en-1-yl)-penta-2-cis/trans, 4-trans-dien-1-oic acid ethyl ester;

3-methyl-5-( l-hydroxy-Z,6,6-trimethyl-4-oxo-cyclohex-2-en-l-yl)-penta-2,4-dien-1-oic acid methyl ester;

3 -methyl-5 1-hydroxy-2, 6,6-trimethyl-4-oxo-cyclohex-2-en-1-yl)-penta-2,4-dien-1-oic acid n-pentyl ester;

3 -methyl-5-( l-hydroxy-Z, 6,6-trimethyl-4-oxo-cyclohex-2-en-l-yl)-penta-2,4-dien-1-oic acid phenyl ester;

3-rnethyl-5-( l-hydroxy-2,6,6-trimethy1-4-oxo-cyclohex-Z-en-l-yl)-penta-2,4-dien-l-oic acid p-nitrophenyl ester;

3-methyl-5-( 1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-1-yl)-penta-2,4-dien-l-oic acid p-methylsulphonylphenyl ester;

3-methyl-5-( 1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-l-yl)-penta-2,4-dien-l-oic acid nitrile;

1-benzoyl-3-methyl-S-(1-hydroxy-2,6,6-trimethy1-4-oxocyclohex-Z-en-l-yl)-penta-2,4diene; and

3-methyl-5-( l-hydroXy-2,6,6-trimethyl-4-oxo-cyclohex-Z-ene-1-yl)-penta-2,4-dien-l-oic acid imidazolide.

DETAILED DESCRIPTION OF THE INVENTION The term halogen as usedthroughout this application includes all four halogens, i.e., bromine,chlorine, fluorine and iodine, if not otherwise indicated. As usedthroughout this application, the term lower alkyl comprehends bothstraight and branched chain saturated hydrocarbon groups containing from1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, etc. Theterm lower alkoxy comprehends lower alkoxy groups containing from 1 to 6carbon atoms such as methoxy, propoxy, ethoxy, etc.

The term lower alkanoyl as utilized throughout this specificationincludes lower alkanoyl groups containing from 1 to 6 carbon atomspreferably 1 to 5 carbon atoms. Among the preferred lower alkanoylgroups are included acetyl, propionyl, pivaloyl.

The term lower alkoxycarbonyl groups includes groups wherein loweralkoxy is defined as above. The preferred lower alkoxycarbonyl groupsare those groups wherein the lower alkoxy substituent contains from 1 to5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or pentoxycarbonyl.

The lower alkyl residue, the lower halo alkyl residues, and the. loweralkyl sulfonyl residues which can be substituted on the phenylsubstituent can contain from 1 through 6 carbon atoms, preferably from 1to 4 carbon atoms. The halo lower alkyl residue can bemonohalosubstituted, dihalo-substituted or trihalo-substituted. Amongthe preferred halo alkyl residues are included chloromethyl,dichloromethyl, and trifluoromethyl. Among the lower alkyl sulfonylresidues are included, methyl sulfonyl, and ethyl sulfonyl.

The carbamyl group can be mono-substituted or disubstituted by loweralkyl. Among the preferred lower alkyl substituted carbamyl groups arethose wherein the lower alkyl substituent contains from 1 to 4 carbonatoms. Among such groups are included methyl carbamyl, N,N- dimethylcarbamyl, ethyl carbamyl and N,N-diethy1 carbamyl.

The X in the compound of Formula II above is an etherified or esterifiedhydroxymethylene group, the hydroxymethylene group can be etherifiedwith a lower alkyl or aryl substituent. On the other hand, thehydroxymethylene group can be esterified with a lower alkanoyloxy oraryloxy group. The term aryl as used throughout the application includesmono-nuclear aryl groups such as phenyl which can be unsubstituted orsubstituted in one or more positions with lower alkyl, halogen or nitro.The term aryl also includes polynuclear aryl groups, such as naphthyl,anthryl, and phenanthryl, azulyl, etc. which may be unsubstituted orsubstituted with one or more of the aforementioned groups. The preferredpolynuclear aryl group is naphthyl.

The compounds of Formula I are hormones for promoting the abscission orshedding of the fruit from a plant and for regulating the growth ofplants. The compounds of Formula I are growth regulators for mono anddicotyledonous plants. Furthermore, because of their low toxicity thesecompounds also can be used as herbicides. The compounds of Formula I arepreferably employed in the cultivation of sugar cane. By applying thesecompounds to sugar cane, the sugar content of the sugar cane can beenhanced since these compounds inhibit the growth of the shoots.

The compounds of Formula I where R is oH=0HiJ=oHx' wherein X is as abovehave the formula wherein X is as above The compounds of Formula I-A canbe produced from compounds of the formula by the following reactionscheme:

(d) v 1x lbs) 101) O Ak/ K/ o o 6 v1 2: its) lo) on T on HO- HO v11 xr1(0) l6) J I x OH F OH 0 O vrrr I-A wherein X 18 as above The compoundof Formula V can be converted to the compound of Formula VI, by areaction step (a) by treating the compound of Formula V with an organicperacid. In carrying out this reaction, any conventional organic peracidcan be utilized. Among the conventional organic peracids which can beutilized, performic acid, peracetic acid, perbenzoic acid,m-chloro-perbenzoic acid and perphthalic acid are preferred. Generally,this reaction is carried out in the presence of an inert organicsolvent. Any conventional inert organic solvent can be utilized incarrying out this reaction. Among the preferred inert organic solvents,the halogenated hydrocarbon solvents such as methylene chloride arepreferred. In carrying out this reaction, temperatures of from --10 C.to

5 room temperature are generally utilized. Generally, it is preferred toutilize temperatures of about C. in carrying out this reaction.

By the process of step (a),4-(2,6,6-trimethyl-cyclohexa-1,3-diene)-but-3-en-2one[dehydro-p-ionone]is converted to 4-(1,2-epoxy-2,6,6-trim'ethyl-cyclohex-3-en-1- yl)-but-3-en-2-one 5,6-epoxy-dehydro-/3-ionone] The compound of Formula VIcan be converted to the compound of Formula VII, via reaction step (b)by treating the compound of Formula V1 with selenium dioxide. Theepoxide of Formula VI and selenium dioxide can, if desired, be employedin equal molar amounts. However, it has been found to be expedient touse the selenium dioxide in a molar excess of the amount of the compoundof Formula VI. Generally, it is preferred to use about 1 mole to about 2moles of selenium dioxide per mole of the compound of Formula VI incarrying out the reaction of step (b). The reaction of step (b) iscarried out preferably in an organic solvent. Any conventional organicsolvent can be utilized. Among the preferred organic solvents areincluded tetrahydrofuran, dioxane, diethyl ether, hexane, benzene, etc.with tetrahydrofuran being especially preferred.

The selenium dioxide, which exists as a solid at room temperature, isadvantageously utilized in a finely divided form, especially in apulverized form. In carrying out the reaction of step (b), temperatureand pressure are not critical and the reaction can be carried out atroom temperature and atmospheric pressure. However, if desired, elevatedor reduced temperatures can be utilized. Generally, it is preferred tocarry out this reaction at a temperature of from 0 C. to the boilingpoint of the reaction mixture. Depending upon the chosen reactiontemperature, from about 12 to 60 hours are suflicient to carry out thereaction of step (b).

The compound of Formula VII can be isolated from the reaction mixture ofstep (b) by the conventional means. These means included extracting witha solvent (particularly diethylether), washing the extract with dilutealkali, drying and thereafter evaporating the ether solvent. Thecompound of Formula VII can, if desired, be purified byconventionalmeans such as adsorption on Kieselgel and elution with asolvent mixture, such as hexane and ethyl acetate. On the other hand,the crude compound of Formula VII can be oxidized to the compound ofFormula VIII.

The oxidation of either the pure or crude compound of Formula VII to thecompound of Formula VIII can be carried out by use of various oxidizingagents. Among the preferred oxidizing agents are included chromium orsulfur trioxide and pyridine, manganese dioxide, chromisulfuric acid,dimethylsulfoxide or N-bromo lower alkanoyl amides. Among the preferredN-bromo lower alkanoyl amides, N-bromoacetamide, is especiallypreferred. In carrying out this reaction any of the conventionalconditions utilized in carrying out oxidation reactions with theseoxidizing agents can be utilized.

From the aforementioned agents, chromisulfuric acid is generallypreferred. In utilizing this oxidizing agent, one expediently uses achromisulfuric acid solution prepared from 26.72 grams of chromiumtrioxide, 23 ml. of concentrated sulfuric acid and water to 100 ml. Thisoxidizing agent is conveniently allowed to act on the compound ofFormula VII at a temperature of from -10 to 10 0., preferably at about 0C. This oxidation can be completed after a few minutes, i.e., after aperiod of from about 5 to 15 minutes. The reaction mixture can be workedup in a conventional manner such as by pouring the reaction mixture ontoice water and extracting with diethyl ether. The ether extract can thenbe washed, dried and the ether evaporated therefrom. If desired, thecompound of Formula VII-I can be purified by adsorption on Kieselgel andeluting with a solvent mixture preferably hexane and ethyl acetate.

On the other hand, the reaction of step (0) can be carried out bytreating the compound of Formula VIII with a dehydrogenating agent.Among the preferred dehydrogenating agents are included aluminumtert.-butylate or a benzoquinone substituted by halogen and/or cyano.Among the preferred dehydrogenating agents for use in this invetion isdichlorodicyanobenzoquinone. The conditions which are commonly employedin utilizing these dehydrogenating agents can be utilized carrying outthe reaction of step (c).

In a further preferred embodiment the diol obtained is oxidized withmanganese dioxide to the desired l-hydroxy-4-oxo compound of Formula I.In the performance of this reaction step the diol is dissolved in aninert organic solvent, for example methylene chloride, manganese dioxideis added and the mixture is shaken, preferably at room temperature. In apreferred embodiment the mixture is shaken for 24 hours and then workedup in a conventional manner.

The compounds of Formulae V, VI, VH, and VIII above can be respectivelyconverted to the compound of Formulae IX, X, XI, and I-A, by either aWittig or Horner reaction. In the reactions of steps (d), (e), (f) and(g) the compounds of Formulae V, VI, VII and VIII are reacted with aWittig reactant of the formula (XIII wherein X" is as X' above with theexception of etherified and esterified hydroxymethylene or formyl, andR' R and R are aryl or di-lower alkylamino; and Y is chlorine, bromineor iodine or with a Horner reactant of the formula t R I CHzX' IV)wherein X' is cayno, carboxy, lower alkoxycarbonyl,

lower alkanoyl and R and R are aryl, aryloxy or lower alkoxy In case acompound of Formulae IX, X, XI or I-A is desired, wherein X is anetherified or esterified hydroxymethylene or a formyl group, therespective compounds of Formulae XXIII, XXIV, XXV or XX are prepared asdescribed hereinafter and the esterified hydroxymethylene compoundobtained may be hydrolyized and, if necessary, etherified or oxidizedwith manganese dioxide to the formyl derivative in conventional manners.

The Wittig or Horner reactions of steps (d), (e), (f) and (g) can becarried out by conventional means well known in the art. Generally,these reactions are carried out in the presence of an alkali metal basein an inert organic solvent. Any conventional alkali metal base can beutilized. The conventional alkali metal bases include the alkali metalhydrides such as sodium hydride, potassium hydride; alkali metal loweralkoxides such as, .sodium methoxide, sodium ethoxide, etc.; and thealkali meta1 amide bases such as, sodamide, potassium amide, sodiummethylamide, potassium methylamide, as-we1l as other alkali metal loweralkyl amides. In carrying out eihter the Horner or Wittig reactions, anyconventional inert organic solvent can be utilized. Generally, solventssuch as benzene, toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide are preferred. In carrying out either the Horner orWittig reactions, temperature and pressure are not critical and thesereactions can be carried out at room temperature and atmosphericpressure. If desired higher or lower temperatures can be utilized.

The conversion of compounds of the Formula IX to compounds of theFormula X, via reaction step (h) is carried out in the same manner asdescribed in connection with step (a). The conversion of compounds ofthe Formula X to compounds of the Formula XI via reaction step (i) iscarried out in the same manner as described in connection with step (b).The conversion of compounds of the Formula XI to compounds of theFormula I-A via reaction step (j), is carried out in the same manner asdescribed in connection with step (c) When X in the compound of theFormula LA is an esterified hydroxymethylene group, this group can besaponified to the corresponding alcohol by conventional saponifyingtechniques such as by treatment with a base. Among the preferred basesfor carrying out this saponification are included alkali metal loweralkoxides such as sodium methoxide.

When X in the compound of Formula I-A is an etherified hydroxymethylenegroup, this group can be converted to the corresponding alcohol byconventional means such as by treating the ether with a concentratedaqueous hydrohalic acid such as hydrogen bromide or hydrogen iodide.This reaction is generally carried out by heating.

When X in the compound of Formula I-A is a lower alkoxycarbonyl,phenoxycarbonyl, or substituted phenoxycarbonyl, this ester can, ifdesired, be converted into amide (which may be lower alkyl substituted).This conversion can be carried out, for example, by treating the esterwith an appropriate dialkylamine lithium compound. The dialkylaminelithium compound needed for this reaction can expediently be prepared bydissolving a dialkylamine (e.g., diethylamine) in diethyl ether andmixing the resulting solution in the cold (preferably at l C. to 20 C.)with a solution of butyl lithium in hexane or tetrahydrofuran andsubsequently allowing this mixture to react. The dialkylamine lithiumobtained is advantageously reacted with the ester at room temperature.

When X, in the compound of Formula I-A above is lower alkoxy carbonyl,phenoxycarbonyl, or substituted phenoxycarbonyl, these esters can beconverted to the corresponding acid by saponification in the mannermentioned hereinbefore. The resulting acids can be converted into acidchlorides by conventional means such as by treatment with thionylchloride, preferably in the presence of pyridine. The acid halide can betransformed into an ester by reaction with a lower alkanoyl, phenol or asubstituted phenol. On the other hand, the acid halide can betransformed into an acid amide by reaction with ammonia, amono-substituted amine, a di-substituted amine or a cyclic amine such asimidazole, utilizing conventional procedures well known in the art.

In accordance with a preferred embodiment of this invention, anintermediate of the formula wherein R is lower alkyl, halo lower alkyl,aryl or aryl substituted with alkyl, halogen or nitro; is converted tothe compound of Formula I wherein X is hydroxymethyl by hydrolysis. Thishydrolysis reaction can take place in the manner hereinbefore describedsuch as by treatment with an alkali. On the other hand, hydrolysis cantake place by treatment with an organic or inorganic acid.

The compound of Formula XX is produced by first reacting a compound ofthe formula:

0 CH: O Hi J-J=CHCH;O &R3

wherein R is as above via a Wittig reaction with a compound of theformula (XXI) (XXII) wherein Y is chlorine, bromine or iodine to producea compound of the formula wherein R is as above.

(XXIII) This Wittig reaction is carried out in the manner describedhereinbefore. The compound of Formula XXIII above is converted to acompound of formula (XXIV) wherein R is as above.

by treatment with an organic peroxide in the manner described inconnection with step (a). The compound of Formula XXIV is converted to acompound having the wherein R is as above by treatment with seleniumdioxide in the manner described in connection with step (b).

The compound of formula XXV is converted to the compound of Formula XXby treatment with an oxidizing agent such as manganese dioxide or any ofthe other oxidizing agents as described in connection with step (c).

The following examples are illustrative of the invention and are not tobe construed as limited thereof. In the examples, all temperatures arein degrees Centigrade. The term concentrated sulfuric acid as utilizedin the examples designates an aqueous solution containing 96% by weightof sulfuric acid. The petroleum ether utilized in these examples had aboiling point of 105 C. The term dilute sulfuric acid as utilized in theexamples is an aqueous solution containing 12% by weight of sulfuricacid.

Example 1 1.5 g. of4-(1,2-epoxy-2,6,G-trimethyl-cyclohex-3-en-lyl)-but-3-en-2-one(designated in the following by 5,6 epoxy-3,4-dehydro-fl-ionone) aretreated with 25 ml. of abs. tetrahydrofuran and, after the addition of 3g. of pulverized selenium dioxide, shaken with nitrogen gassing for 12hours. The reaction mixture is thereupon diluted with 100 ml. of diethylether and then filtered. The filtrate is successively washed with 0.5 Naqueous sodium hydroxide and water, dried over sodium sulphate andevaporated under reduced pressure to produce 4-(1,4-dihydroxy 2,6,6trimethyl-cyclohex-Z-en-l-yl)-but-3-en-2- one as a yellow oil.

Example 2 The yellow oil 4(1,4-dihydroxy-2,6,G-trimethyl-cyclo-'heX-Z-en-I-yl)-but-3-en-2-one is taken up in 50 ml. of acetone andsubsequently treated at 0 C. with 1.13 ml. of a 'chromic acid solution(26.72 g. of chromium trioxide, 23 ml. of cone. sulphuric acid, water to100 ml.). After 5 minutes, the reaction mixture is poured onto ice andextracted with diethyl ether. The ether extract is successively washedwith a saturated aqueous sodium bicarbonate solution and with water,dried over sodium sulphate and evaporated under reduced pressure. Theresidual oily yellow-colored 4 (1hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-1-yl)-ut-3-en-2-one ispurified by adsorption on the 100-fold amount of Kieselgel (elutingagentzhexane/acetic acid ethyl ester 1:2). After recrystallization frombenzene/hexane, the compound melts at 112 C.

Example 3 19 g. of 4-(2,6,6-trimethyl-cyclohex-1,3-dien-1-yl)-but-3-en-2-one(3,4-dehydro-B-ionone) are dissolved in 300 ml. of methylenechloride and, with stirring at 3 to 5 0., treated little by little with23.5 g. of m-chloroperbenzoic acid. The reaction mixture is furtherstirred at C. for 2 hours, then poured into a mixture of 300 ml. oficewater and 46 ml. of 3 N aqueous sodium hydroxide The methylenechloride layer is separated off and washed neutral with Water. Theaqueous phase is exhaustively extracted with diethyl ether. The etherextract obtained, together with the methylene chloride phase, is driedover sodium sulphate and evaporated under reduced pressure. The residuallight-yellow colored oily 5,6-epoxy-3,4-dehydro-fi-ionone is purified byadsorption on the 50-fold amount of Kieselgel (granule size 0.2-0.5mm.). (Eluting agent: hexane/acetic acid ethyl ester 7:2 parts byvolume.)

Example 4 3.2 g. of3-methyl-5-(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1-yl) penta 2cis/trans, 4-trans-dien-1-oic acid ethyl ester are introduced into 50ml. of tetrahydrofuran and, after the addition of 6.4 g. of seleniumdioxide shaken at room temperature for 48 hours. The reaction mixture isthereupon diluted with 150 ml. of diethyl ether and filtered clear. Theethereal solution is washed three times With cold 0.5 N aqueous sodiumhydroxide and subsequently three times with water, dried over sodiumsulphate and evaporated under reduced pressure. There resulted3-methyl-5- 1,4-dihydroxy-2,6,6-trimethylcyclohex- 2-en-l-yl)penta-Z-cis/ trans, 4-trans-dien-1-oic acid ethyl ester as a yellow oil.

Example 5 3.4 g. of 3-methyl-5-(l,4-dihydroxy 2,6,6trimethylcyclohex-Z-en-l-yl) penta 2 cis/trans, 4-trans-dien-loic acidethyl ester are dissolved in 100 ml. of acetone and treated at 0 C. with4.33 ml. of a chromic acid solution (26.72 g. of chromium trioxide, 23ml. of conc. sulphuric acid, Water to 100 ml.). After 5 minutes, thereaction mixture is poured onto ice and extracted with diethyl ether.The ether phase is washed With saturated aqueous sodium bicarbonatesolution then with water, dried over sodium sulphate and evaporatedunder reduced pressure. The residual dark-yellow oily3-methyl-5-(1-hydroxy-Z,6,6-trimethyl-4-oxo-cyclohex-2-en-l-yl) penta-2-cis/trans, 4-trans-dien-1-oic acid ethyl ester can subsequently besaponified as follows without further purification.

Example 6 After the addition of a solution of 10 g. of potassiumhydroxide in 70 ml. of methanol and 30 ml. of water, 2.9 g. of3-methyl-5-(1-hydroxy-2,6,6-trimethyl 4oxocyclohex-Z-en-1-yl)penta-2-cis/trans, 4 trans-dien-l-oic acid ethylester are stirred at room temperature for 24 hours. The reaction mixtureis subsequently concentrated under reduced pressure. The concentrate istaken up in Water and extracted with diethyl ether. The aqueous phase isslightly acidified with dilute sulphuric acid and again extracted withdiethyl ether. The last-obtained ether extract is washed three timeswith water, decolorized with the aid of active charcoal, dried oversodium sulphate and treated with high-boiling petroleum ether up toincipient crystallization. The 3-methyl-5-(1-hydroxy-2,6,6- trimethyl 4oxo cyclohex-Z-en-l-yl) penta 2 cis-4- trans-dien-l-oic acid whichprecipitates melts at 185- 186 C.

1 0 Example 7 3.85 g. of sodium hydride (50% by weight suspension inmineral oil) are overlaid with 150 ml. of abs. dioxan and treateddropwise at 10 C. with 31 g. of di(2-chlorophenyl)-ethoxy-carbonylmethyl phosphine oxide. The mixture is stirred at room temperature for30 minutes, then again cooled to 10 C. and treated dropwise with asolution of 15 g. of 5,6-epoxy 3,4 dehydro-B-ionone (manufacturedaccording to Example 3) in 20 ml. of dioxan. The reaction mixture isstirred at room temperature for 12 hours, and after decomposition of theexcess sodium hydride by cautious addition of ethanol, poured into anice/ sodium chloride mixture and exhaustively extracted with diethylether. The ether extract is washed with water, dried over sodiumsulphate and evaporated under reduced pressure. The residual yellow,oily 3-methyl 5 (1,2 epoxy-2,6,6-trimethyl-cyclohex-3-en-1-yl)-penta-2-cis/trans, 4-trans-dien-1-oic acid ethyl ester is purified byadsorption on the -fold amount of Kieselgel (eluting agent: hexane/acetic acid ethyl ester 7:1 parts by volume). B.P. about 165 C./0.05 mm.Hg.

Example 8 6 g. of 3-methyl-5-(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1-yl)-penta-2-cis, 4-trans-dien-1-oic acid methyl ester aredissolved in ml. of dioxan and, after the addition of 5 g. of pulverizedselenium dioxide, stirred at room temperature for 50 hours. The reactionsolution is filtered clear. The filtrate is diluted with 250 ml. ofhexane and, after the addition of 6.2 g. of mercury (II) chloride,intensively stirred in ml. of water for 5 hours. The mixture issubsequently filtered. The filtrate is diluted with diethyl ether,Washed neutral with Water, dried over sodium sulphate and evaporatedunder reduced pressure. The residual isomer mixture consisted of3-methyl5-(l,4- cis-dihydroxy 2,6,6 trimethyl-cyclohex-Z-en-l-yl)-penta-2-cis, 4 trans dien-l oic acid methyl ester and 3-methyl-5-(1,4-trans-dihydroxy 2,6,6 trimethyl-cyclohex-Z-en-lyl)-penta 2 cis,4-trans-dien-1-oic acid methyl ester.

Example 9 6.3 g. of the isomer mixture of 3-methyl-5-(1,4-cis/trans-dihydroxy 2,6,6 t-rimethyl-cyclohex-Z-en-l-yl)- penta-Z-cis,4-trans-dien1-oic acid methyl ester are dissolved in 150 ml. of acetoneand treated at 0 C. with 8.45 ml. of a chromic acid solution (26.72 g.of chromium trioxide, 23 ml. of cone. sulphuric acid, water to 100 ml.).After 10 minutes, the reaction mixture is poured onto ice and extractedwith diethyl ether. The ether extract is washed With a saturated aqueoussodium bicarbonate solution and with water, dried over sodium sulphateand evaporated. The residual yellow oily 3-methyl- 5-(1 hydroxy 2,6,6trimethyl-4-oxo-cyclohex-2-en-1- yl)-penta-2-cis, 4 trans-dien-l-oicacid methyl ester is purified by adsorption on the 40-fold amount ofKieselgel eluting agent: hexane/ acetic acid ethyl ester 1:1 parts byvolume). After recrystallization from high-boiling petroleum ether withthe addition of a little diethyl ether, the ester melts at 96 C.

Example 10 After the addition of a solution of 6 g. of potassiumhydroxide in 45 ml. of methanol and 15 ml. of Water, 1.8 g. of3methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-n-1-yl)-penta-2-cis,4-trans-dien-1-oic acid methyl ester are stirred at room temperature for12 hours. The reaction mixture is thereupon diluted with water. Theaqueous phase is exhaustively extracted with diethyl ether. The waterphase is slightly acidified with dilute aqueous sulphuric acid andextracted with diethyl ether. The last-obtained ether extract is washedthree times with water, dried over sodium sulphate and evaporated underreduced pressure. The residual 3-methyl-5-(1-hydroxy- 2,6,6trimethyl-4-oxo-cyclohex-2-en-l-yl)-penta-2-cis, 4-

1 1 transdien-l-oic acid melts at 187-188 C. after recrystallizationfrom hexane/diethyl ether.

Example 11 6 g. of 3-methyl-5-(2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)-penta-2-cis, 4-trans-dien-l-oic acid methyl ester [prepared fromdi(2-chlorophenyl)-methoxycarbonyl-methylphosphine oxide and5,6-epoxy-3,4-dehydro-B-ionone as described in Example 9] are dissolvedin 60 ml. of methylene chloride and treated dropwise at 0 C. with asolution of 5.3 g. of m-chloro-perbenzoic acid in 60 ml. of methylenechloride. The reaction mixture is further stirred at 0 C. for 90minutes, then poured into a mixture of ice and ml. of 3 N aqueous sodiumhydroxide. The methylene chloride layer is separated off, washed withwater, dried over sodium sulphate and evaporated under reduced pressure.The residual yellow, oily 3-methyl-5-(l,2epoxy-2,6,6-trimethyl-cyclohex-3-en-l-yl) -penta-2-cis, 4- trans-l-oicacid methyl ester can be purified by adsorption on the 40-fold amount ofKieselgel (eluting agentzhexane/ acetic acid ethyl ester 9: 1).

Example 12 29 g. of 3-methyl-5-(2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)-penta-2,4-dien-1-al was dissolved in 50 ml. of methylene chlorideand at 0 2.3 g. of m-chloroperbenzoic acid were added. The temperaturerose to 8. The reaction mixture was allowed to stand at 0 for 1 hour andthen poured onto ice and 5 ml. of 3 N aqueous sodium hydroxide. Afterextraction with ether, the organic phase was washed with water, driedand evaporated to dryness. The crude product was chromatographed on40-fold amount of aluminum oxide [neutral, activity grade III (Woelm)with hexane/acetic acid ethyl ester (6:1)].

The crude, light yellow oil was used directly for the next step asdescribed in Examples 1, 4 and 14.

Example 13 By the procedure of Examples 1, 2 and 3:

3-methyl-5-(2,6,6 trimethyl-cyclohexa 1,3-dien-l-yl)-penta-2,4-dien-1-oic acid n-pentyl ester is converted to 3methyl-5-(l,2-epoxy-2,6,6trimethyl-cyclohex-3-en-1-yl)-penta-2,4-dien-l-oic acid n-pentyl ester, which then is convertedto 3-methy1-5-( l-hydroxy-2,6,6-trimethyl4-oxo-cyclohex-2-en-1-yl)-penta-2,4-dien-1-oic acid n-pentyl ester(oil);

3 methyl 5 (2,6,6-trimethyl-cycl0hexa-1,3-dien-l-yl)-penta2,4-dien-1-0ic acid phenyl ester is converted to 3- methyl5-(l,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1- yl)-penta-2,4-dien-1-oicacid phenyl ester which then is converted to3-methyl-5-(l-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-Z-en-l-yl)-penta-2,4-dien-1-oic acid phenyl ester (M.P.l46147 C.);

3-methy1 5 (2,6,6-trimethyl-cyclohexa-1,3-dien-l-yl)-penta-2,4-dien-l-oic acid p-nitrophenyl ester is converted to3-methyl-5-(l,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1-yl)-penta-2,4-dien-1-oic acid p-nitrophenyl ester which then is convertedto 3-methyl-5-( l-hydroxy- 2,6,6-trirnethyl 4oxo-cyclohex-Z-en-1-yl)-penta-2,4- dien-l-oic acid p-nitrophenyl ester(M.P. 158-163 3 methyl 5 (2,6,6-trimethyl-cyclohexa-1,3-dien-1-y1)-penta-2,4-dien-1-oic acid p-methyl sulfonyl-phenyl ester is converted to3-methyl-5-(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-l-yl)-penta-2,4-dien-1-oicacid prnethyl sulfonyl-phenylester which then is converted to 3methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-1-yl)-penta-2,4-dien-1-oic acid-p-methyl, sulfonylphenylester (M.P.161-166" C.);

3 methyl 5 (2,6,fi-trimethyl-cyclohexa-1,3-dien-l-y1)-penta-2,4-dien-l-oic acid-nitrile is converted to 3-methyl-5-(1,2-epoxy2,6,6 trimethyl-cyclohex-3-en-1-yl)- penta-2,4-dien-1-oic acid-nitrilewhich then is converted to 3methyl-5-(1-hydroxy-2,6,6trimethyl-4-oxo-cyclo- 12hex-Z-en-l-yl)-penta-2,4-dien-l-oic acid-nitrile (M.P. 172-173 C.);

1 benzoyl 3 methyl-5-(2,6,6-trimethyl-cyclohexa-1,3-dien-l-yl)-penta-2,4-dien is converted to 1-benzoyl-3- methyl 5(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-lyl)-penta-2,4-diene which thenis converted to 1- benzoyl3-methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-Z-en-l-yl)-penta-2,4-dien (oil) 3 methyl 5(2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)- penta-2,4-dien-1-oicacid-imidazolide is converted to 3- methyl 5(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-lyl)-penta-2,4-dien-l-oicacid-imidazolide which then is converted to3-methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-Z-en-1-yl)-penta-2,4-dien-l-oic acid-imidazolide (M.P.165-175 C.); and- 3 methyl 5 (2,6,6-trimethyl-cyclohexa-1,3-dien-l-yl)-penta-2,4-dien-1-al is converted to 3-methyl-5-(1,2- epoxy 2,6,6trimethyl-cyclohex-3-en-l-yl)-penta-2,4- dien-l-al which then isconverted to 3-methyl-5-(l-hydroxy2,6,6-trimethyl-4-oxo-cyelohex-2-en-l-yl) -penta- 2,4-dien-1-al (M.P.113-415 (3.).

Example 14 In 60 ml. of tetrahydrofuran, there was dissolved 2.8 g. of3-methyl-5- 1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1-yl)-penta-2,4-dienyl acetate. After the addition of 6.5 g. of seleniumdioxide, the mixture was allowed to stand for 45 hours at roomtemperature. After this period, the

reaction mixture was diluted with 150 ml. of diethyl ether and filtered.The ether solution was washed 3 times with 0.5 N aqueous sodiumhydroxide and then 3 times with water. The reaction mixture was thendried over sodium sulfate and then evaporated under vacuum. Afterevaporation, there resulted 3 methyl5-(1,4-dihydroxy-2,6,6-trimethyl-cyclohex-Z-en-1-yl)-penta-2,4-dienyl acetate as a crudeoil.

Example 15 In ml. of methylene chloride there was dissolved 3 g. of3-methyl-5-(1,4-dihydroxy-2,6,6-trimethyl-cyclohex-2-en-1-yl)-penta-2,4-dienylacetate and 30 g. of manganese dioxide. The resulting reaction mixturewas shaken for 24 hours at room temperature. After this period, thereaction mixture was filtered and then evaporated to dryness undervacuum. From the resulting oily product, 3 methyl 5-(1-hydroxy-2,6,6-trimethy1-4-oxo-cyclohex-Z-en-l-yl)-penta-2-eis-4-trans-dienyl acetate was obtained. This productwas obtained in crystalline form by fractional crystallization from amixture of hexane and diethyl ether. The resulting product had a meltingpoint of 100-101 C.

Example 16 In 20 ml. of methanol, there was dissolved 2 g.-'of 3 methyl5 (1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-1-yl)-penta-2-cis-4-trans-dienyl acetate. After the addition of 15g. of sodium hydroxide in 5 ml. of water to the solution, the reactionmixture was allowed to stand for one hour at room temperature underconstant stirring. After this, 100 ml. of water were added to thesolution and the solution was extracted with diethyl ether. Theresulting ether solution was washed neutral with water and then dried byevaporation under vacuum. From the residue, the product3-methyl-5-(l-hydroxy-2,6,6-trimethyl- 4 oxocyclohex-Z-en-l-yl)-penta-2-cis-4-trans-dien-1-'o1 was crystallizedutilizing a mixture of hexane and acetic acid ethyl ester. The producthad a melting point of 126- 128 C.

Example 17 50 g. of 3,4-dehydro-cyclogeranyl-triphenyl phosphoniumbromide, which was obtained by reacting equimolar amounts of3,4-dehydro-cyclogeranyl bromide(l-bromomethyl-2,6,6-trimethylcyclohexa-1,3-diene) with triphenylphosphine, was dissolved in 250 ml. of dimethyl formamide. To theresulting solution there was added a solution containing 2.3 g. ofsodium in 75 ml. of absolute alcohol. After the sodium ethoxide solutionwas added, 14 g. of 3-formyl-2-buteny1 acetate in 20 ml. of dimethylformarnide was added to the reaction mixture. The resulting reactionmixture was stirred for 5 hours at C. and then acidified with a dilutesulfuric acid solution. There resulted a light yellow oily suspensionwhich was extracted with hexane. The hexane extract was washed neutralwith water and then dried over sodium sulfate. The solvent was removedfrom the reaction medium by evaporation ultilizing vacuum. Afterevaporation, a light oil resulted. This oil was purified by adsorptionon Kieselgel and eluting with benzene. The resulting product was 3methyl (2,6,6-trimethyl-cyclohexa-1,3-diene-1-yl)- penta-2,4-dienylacetate.

Example 18 In 200 ml. of methylene chloride there was dissolved 12 g. of3-methyl-5-(2,6,6-trimethyl-cyclohexa-l,3-dien-1- yl)-penta-2,4-dienylacetate. The resulting solution was cooled to 0 C. At this temperature5.6 g. of m-chloroperbenzoic acid was added portionwise. The reactionmixture was allowed to stand for 60 minutes at 0 C. under constantstirring and poured on a mixture of ice and 20 ml. of 3 N aqueous sodiumhydroxide. After this period, the methylene chloride phase was separatedand washed with water. After. washing, this phase was dried over sodiumsulfate and evaporated under reduced pressure. After evaporation thereresulted 3-methyl-5-(1,2-epoxy-2,6,fi-trimethyl-cyclohex-3-en-l-yl)-penta-2,4-dienyl acetate as ayellow oil. This yellow oil was purified by adsorption on a 50 foldamount of Kieselgel (eluting agent: hexane/acetic acid ethyl ester :1parts by volume).

Example 19 In the manner of Examples 18, 14 and 3 methyl 5(2,6,S-trimethyl-cyclohexa-1,3-dien-1-yl)- penta-2,4-dienyl benzoate wasconverted to 3-methyl-S- (1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1- yl)penta- 2,4-dienyl benzoate which then was converted to 3methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en-l-yl)-penta-2,4-dienyl benzoate (M.P. 105);

3 methyl 5 (2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)-penta-2,4-dienyl-2,4'-dinitro benzoate was converted to3-methyl-5-(1,2-epoxy-2,6,6-trirnethyl-cyclohex-3-enl-yl)-penta-2,4-dienyl-2',4'-dinitrobenzoate which then was converted to 3-methyl-5-(1-hydroxy-2,6,6trimethyl-4-oxo-cyclohex-2-en-1-yl)-penta-2,4-dienyl- 2,4' dinitrobenzoate (M.P. 130-131");

3 methyl 5 (2,6,6-trimethyl-cyclohexa-1,3-dien-l-yl)- penta-2,4-dienylnaphthoate was converted to 3-methyl- 5-1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-l-yl) penta- 2,4-dienylnaphthoate which then was converted to 3met-hy1-5-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex- 2en-1-yl)-penta-2,4-dienyl naphthoate (M.P. 126- 127 14 3 methyl 5(2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)- penta-2,4-dienyl-4-methylbenzoate was converted to 3 methyl-5-(1,2-epoxy-2,6,6-trimethyl-cyc1ohex-3-en-1-yl)-penta-2,4-dienyl-4'-methyl benzoate which then was converted to3-methyl-5-(l-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-en1-yl)-penta-2,4-dienyl-4'-methyl benzoate (M.P. 119);

3 methyl 5 (2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)-penta-2,4-dienyl-4'-chloro benzoate was converted to 3 methyl-S-1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1-yl)-penta-2,4-dienyl-4'-chloro benzoate which then was converted to3-methyl-5-(1-hydroxy-2, 6,6-trimethyl-4-oxo-cyclohex-Z-en-l-yl)-penta-2,4-dienyl-4'-chloro benzoate (M.P. 123);

3 methyl 5 (2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)-penta-2,4-dienyl-4-nitro benzoate was converted to 3 methyl-S-1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1- yl)-penta-2,4-dienyl-4'-nitrobenzoate which then was converted to3-methyl-5-(1-hydroxy-2,6,6-trimethyl-4- oxo cyclohex-Z-enl-yl)-penta-2,4-dienyl-4-nitro 'benzoate (M.P. -136);

3 methyl 5 (2,6,6-trimethyl-cyclohexa-1,3-dien-1-yl)-penta-2,4-dienyl-chloro acetate was converted to 3-methyl 5(1,2-epoxy-2,6,6-trimethyl-cyclohex-3-en-1-yl) penta-2,4-dienyl-chloroacetate which then was converted to3-methyl-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex 2en-l-yl)-penta-2,4-dienyl-chloro acetate (M.P. 99-100).

Example 20 All of the products in Example 19 were utilized by theprocedure of Example 16 to produce 3-methyl-5-(1-hydroxy 2,6,6trimethyl-4-oxo-cyclohex-2-en-1-yl)-penta- 2,4-dien-1-ol.

We claim:

1. A compound of the formula wherein R is lower alkyl, halo-substitutedlower alkyl, hydrocarbon aryl or hydrocarbon aryl substituted with loweralkyl, halogen or nitro.

2. The compound of claim 1 wherein said compound is 3 methyl 5(2,6,6-trimethyl-cyclohexa-1,3-dien-l-yl)- penta-2,4-dieny1 acetate.

References Cited Chem. Abstracts, 7 3:88039k.

VIVIAN GARNER, Primary Examiner US. Cl. X.R.

260309, 348 A, 348 C, 464, 468 R, 469, 470, 471 R, 476 R, 487, 488 H,491, 514 R, 586 R, 589, 592, 598

